University Times

Last May, an asthma drug clinical trial at Johns Hopkins University resulted in the death of a healthy 24-year-old study volunteer.

The woman's death received national attention, in part because the study's sponsoring institution was Johns Hopkins, the top recipient of federal research dollars among the nation's medical institutions.

An internal review of the asthma drug clinical trial concluded that the researcher, an associate professor of immunology, had made missteps in the study, including failing to uncover research from the 1950s that suggested the drug he was testing could be toxic to human lungs.

The Office of Human Research Protections (OHRP), a division of the U.S. Department of Health and Human Services, temporarily shut down most of the 2,400 federally funded human clinical trials at Johns Hopkins, pending a university plan targeting problems identified by OHRP.

Those problems included charges that the Johns Hopkins Institutional Review Board (IRB) — the federally required group designated at each research university to approve clinical trials — was not considering each proposal thoroughly enough.

OHRP eased the suspension in July after reviewing the Hopkins corrective plan, although the office ordered that the majority of clinical trials be reviewed again before continuing.

Partly in response to the problems at Johns Hopkins and, in recent years, comparable incidents at Duke and Penn, Pitt's Institutional Review Board, in conjunction with its Office of University Counsel, commissioned a confidential evaluation of the human clinical trials review process here.

Dennis Swanson, director of Pitt's IRB, said, "The OHRP has never done a random or for-cause evaluation of Pitt's IRB. We were looking for quality assurances after the Johns Hopkins problem. At our request, [the General Counsel] hired an auditor to come in and look at our procedures."

Swanson declined to discuss the specifics of the evaluation. "What I will say is that I think we're really doing a good job." Swanson, who has responsibility for the day-to-day administration and operation of Pitt's IRB office, added that IRBs do not have an external accrediting organization in the manner of schools and academic programs, although that's been recommended by a number of sources.

Theresa Colecchia, University associate general counsel, said the consultant Pitt brought in was a medical official from a research institution similar to Pitt, with an academic medical school and interconnected hospital system. The site visit was done over several days last fall, Colecchia said.

"We did not do this for any specific problems," she said. "We wanted to take a voluntary diagnostic look at overall compliance of Pitt's IRB. This man had experience with OHRP procedures and audits. We asked him, essentially, to pretend that he was a representative of the OHRP, to evaluate us through their eyes."

Colecchia also declined to discuss specifics of the evaluation, noting that the consultant insisted on anonymity and that the findings be kept confidential.

S. Clifford Schold, Pitt's assistant vice chancellor for clinical research, Health Sciences, said of the John Hopkins incident, "It wasn't so much the unfortunate outcome for a volunteer of a study, which everyone regrets. There's going to be a finite risk of something bad happening with any research study. The real problem was [Johns Hopkins's] review process for the protection of human subjects."

Pitt's response, Schold continued, "was to make sure we were in compliance with federal rules and regulations on protection of human subjects, which have gotten more complex over time. I'm confident that we're in full compliance."

Schold said the IRB's federal compliance function is administratively separate from the researcher's basic research function, a system of checks and balances that works well. "The job of the faculty is to do research;the IRB's job is to protect human subjects. There's always going to be a tension there, but that's basically a healthy tension," he said.

Schold characterized clinical trials as "the only avenue for determining the safety and efficacy of the ever-growing number of new [drugs] now flowing out of the nation's laboratories. It is not simply desirable but essential that every effort be made to increase patients' awareness of opportunities to enroll in clinical trials, for if we don't have adequate participation, we surely can't make the most of the exciting advances now being witnessed in medical science."

(See related story, page 7.) Hand in hand with that effort is the necessity to protect the health and safety of human subjects, Schold added.

According to Swanson, all human subject research at Pitt — everything from questionnaires and surveys to complex drug trials and bio-medical interventions — requires IRB approval. "I would estimate there are 2,500 to 3,000 projects going on at any one time, involving about 500 Pitt faculty," he said. "We approve about 1,400 to 1,450 new research projects annually."

Pitt's Institutional Review Board has five committees of 18-20 members each, most of them physicians and nurses representing a number of research areas at Pitt such as psychiatry, oncology and cardiology, Swanson said. "Also, there are non-scientific-based people and required non-institution-affiliated members who focus particularly on informed consent documents, that they be readable and understandable by those who are potential clinical trials participants," he said.

Helping the researcher As an indication of the emphasis placed on clinical research by Pitt, the University recently established the Office of Clinical Research (OCR), which Schold heads, to expedite the IRB approval process.

"The OCR was established for the purpose of facilitating and promoting high-quality research by the faculty at the University," Schold said. "We work closely with the IRB, but we're distinct from them. In a sense, we want to be the advocates for the faculty who want to do clinical research. When they come to us pulling their hair out and saying, 'We don't know what to do to get this through the IRB,' the OCR acts as the communicator between them and the IRB."

The OCR is organized into four operational units giving researchers specialized resources to help with planning and implementing clinical research. These units are the:

* Clinical research support unit, which guides the investigator and the research team through regulatory requirements, assists in subject identification and recruitment and provides an independent safety monitoring committee for studies in progress.

* Education unit, which assists with the coordination and development of educational programs in clinical research on the Pitt campus.

* Information management unit, which coordinates information management services for clinical research across the Schools of the Health Sciences by facilitating communication between various database and information technology systems used by the schools.

* Sponsored clinical trials unit, which establishes relationships between the Schools of the Health Sciences and sponsors of clinical trials that include industry, government and foundations and which promotes clinical trials and funding opportunities sponsored by federal agencies.

"By providing a broad infrastructure offering support to all clinical researchers, we cannot only more efficiently facilitate existing research and help our researchers, we can be more supportive to young investigators," Schold said.

A question of perception Schold acknowledged that in recent years clinical research has received a bad name among the general population. "Occasionally, it's because there's a 'bad apple' researcher," Schold said. "But in some ways even more egregious than that has been a series of reports showing that physicians or other health care professionals are basically profiting from doing clinical research, and the fact that that appears to be their primary motivation."

Schold said Pitt takes great pains to review the financial terms of all research proposals.

"Now, let's be clear: clinical research is expensive; there are a lot of legitimate expenses that come into play when clinical research is being done, and drug companies or device companies recognize this," Schold said. "They consider those expenses an investment in developing new treatments."

On the other hand, money shouldn't be the main motivation of the investigator, Schold said. "It's very important to us in the Office of Clinical Research that clinical investigators have as their primary motivation the advancement of knowledge and are seeking to get their costs covered, not to profit. There's attention paid to that in addition to the straightforward issues of potential harm to participants."

Recruiting for clinical trials Just as financial gain shouldn't be the motivation for researchers, compensation is rarely the prime motive for clinical trial volunteers, Schold said. He said that compensation for a volunteer is usually tied to the amount of time a participant commits to and reimbursement of travel expenses. Moreover, he said, it's considered an inappropriate inducement to overpay people to sign up for a trial.

"That's one thing that the IRB scrutinizes. Some of these treatments are potentially toxic, and if you're offering more and more money, you're basically saying, 'What is it going to take for you to accept the risk when this might have some adverse effect on you?' and that just doesn't smell good. My personal experience is that, more often than not, people sign up to participate in clinical research because they think it's the right thing to do; because they know it will help us get the right answer faster. They want to help advance the field," Schold said. Often participants have personal experience, either themselves or a family member, with a disease.

For patients with certain rare diseases, Schold added, the best treatments might only be available in a clinical trial, because the treatments haven't been approved yet by the U.S. Food and Drug Administration.

Once a research project secures IRB approval, the subject recruitment process can begin. "Sometimes the doctor might have a built-in population with a certain disease and all he or she has to do is to contact those people," Schold said. "Other times it's a relatively uncommon disease and they have to go out to identify patients who might be appropriate, and that's where you see the bus signs and the other advertisements recruiting subjects."

Most clinical trials also need control groups, Schold said. "Typically, some members of the tested population are given a placebo, and neither the physician nor the patient knows what they're getting. That's what's called a blind study," he said.

Other trials involve testing certain antibiotics that are expected to have relatively low incidences of side effects on control groups of normal volunteers.

"Usually by the time you get to a randomized trial, there's a population of patients who have received the drug," Schold said. "In other words, when you first start giving it, you give it in a very low dose, make sure it's safe, then you assess appropriate dosage, assess the possible side-effects and if it passes all those screens, only then do you start evaluating it against a disease. By the time you get to that point, the informed consent form would say, 'of the 300 people who took this drug, 2 percent got a rash, 5 percent had a stomach ache,' and you list all those data."

Other elements in informed consent include: information on compensation; information on how the study could effect potentially fertile parents or pregnant women, and information on available alternative treatments.

Sometimes, the information on the consent form dissuades volunteers from entering a study. "If that's the case, that's fine," Schold said. "More often than not though, by the time you get to that stage, they are usually motivated enough that if they talk it through and they understand it completely, they go ahead with it. This is the way we advance our knowledge — through properly conducting clinical research — and we need people who want to participate in studies."

–Peter Hart